Existing data support a critical role of neurokinin 1 receptor (NK1 receptor) expressing neurons in the dorsal spinal cord in mediating pain processing. Taking the advantage of newly developed nanoparticles, we propose to study in this exploratory proposal whether conjugation of nanoparticles with Substance P, a pain- inducing peptide and specific ligand to NK1 receptors, can achieve cell-type specific delivery of small interference RNA (siRNA) into NK1 receptor expressing cells upon ligand-induced endocytosis, and if so, whether this approach can lead to effective gene silencing and pain relief in animal models. We will first study the optimal dose and time point for nanoparticle distributio in vivo. Second, we will examine nanoparticle distribution in different cell types. Third, we wil examine if this approach can be used for in vivo NK1 receptor gene silencing and blocking pain processing in animal models. Promising data derived from this project will be used for the application of a larger scale NIH R01 project related to application of siRNA/nanoparticles in targeted gene silencing and pain relief. PUBLIC HEALTH RELEVANCE: Chronic pain is a common clinical syndrome lacking specific, effective and safe therapeutic agents. Taking the advantage of newly developed nanoparticles, we plan to study whether conjugation of a ligand specific to pain-mediating receptors to nanoparticles can improve cell-type specific delivery of small interference RNA (siRNA) for effective gene silencing and pain relief in vivo. Completion of this study will allow us to gain insights into the potential use of nanoparticles as a carrier for cell-type specific drug delivery n vivo.